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A triplet repeat expansion in the Fragile X gene is a common cause of inherited mental retardation. Only recently, researchers recognized that a shorter expansion, formerly regarded as an innocuous precursor to the disease-causing mutation, brings its own trouble. Years of follow-up with Fragile X families led to the realization that the affected children’s grandfathers, who carried the mid-length expansion and had normal cognitive development, had a high incidence of an age-related Parkinson-like condition named Fragile X tremor/ataxia syndrome (see ARF related news story). Surprisingly, the developmental disorder and the neurodegenerative disease have no clinical symptoms in common even though they stem from the same gene. Their mechanistic underpinnings are different, as well: mental retardation results from loss of expression of the Fragile X protein, while the tremor/ataxia syndrome (FXTAS) is associated with the production of high levels of Fragile X mRNA.

In two papers out in the August 16 issue of Neuron, researchers report just how the triplet-expanded RNA causes FXTAS: the repeats act as sponges that soak up RNA-binding proteins required for normal production and translation of other cellular mRNAs. The work, from Stephen Warren’s lab at Emory University School of Medicine in Atlanta, Georgia, and Juan Botas and David Nelson and colleagues at Baylor College of Medicine in Houston, Texas, explains how different alleles of one gene can cause distinct diseases that hit at different stages of life.

The CGG expansion in the 5’ untranslated region of the Fragile X gene comes in three types. With fewer than 60 repeats, people are normal. When the repeat number exceeds 200, the protein no longer gets expressed, resulting in the Fragile X mental retardation. People who fall in between (55 to 200 repeats) produce an mRNA with an expanded CGG tract, which has been implicated in FXTAS.

In support of the sequestration hypothesis, the Warren group previously showed that overexpression of an RNA containing 90 CGG repeats could induce neurodegeneration in fruit flies (Jin et al., 2003). In their present paper, coauthors Peng Jin and Ranhui Duan from the Emory group report the purification of proteins from brain extracts that bind to the same expanded repeat. The second paper, with first author Oyinkan Sofola plus Jin, describes a genetic approach to survey genes for RNA-binding proteins that affect the neurotoxicity of the expanded RNA in flies. Together, the efforts identified the RNA binding protein Pur α and a complex of two proteins, CUGBP1 and hnRNP A2/B1, as binding partners for the CGG repeats. Overexpression of either Pur α or CUGBP1 protein could suppress neurodegeneration in the fly model, consistent with the sequestration model. Interestingly, the Warren group found that the Pur α protein was also present in nuclear inclusions in brain tissue from people with FXTAS.

”These findings provide good evidence that each RNA-binding protein has a role in the pathogenesis of FXTAS,” write Maurice Swanson of the University of Florida in Gainesville and Harry Orr of the University of Minnesota in Minneapolis in an accompanying commentary. FXTAS is the second degenerative disease for which a pathogenic RNA triple expansion has been implicated (the first was myotonic dystrophy, an adult-onset muscle disease), suggesting that such RNAs may play a role in other diseases, as well.

In a wider context, the results serve as a reminder that one gene can cause multiple forms of disease. In the AD arena, for example, researchers unexpectedly identified a presenilin mutation in a person with a three-generation family history of late-onset disease (see ARF related news story). The mutation, which is typically associated with early onset AD, appears in this case to lead to a late-onset form, suggesting that some PS mutations can cause AD with a large range in age of onset, both early and late.—Pat McCaffrey